Reacción a "An investigation alleges that the death of a girl in China was covered up after she was given an experimental gene therapy"

Just over a year ago, we learnt of the case of a boy born with a very serious metabolic disorder (a deficiency in a key enzyme in the urea cycle, called carbamyl phosphate synthetase 1, which is absolutely essential for removing ammonia from the body and detoxifying it) who was treated during his first few months of life with an experimental therapy based on CRISPR base editors and managed to survive, thus avoiding the certain death he was heading towards, just like any other child born with similar mutations in the same gene.

Therapeutic interventions for individual patients do not always end in success. In late 2022, we learnt of the case of a boy in the US with Duchenne muscular dystrophy in an advanced stage who received an experimental treatment, following approval for compassionate use by the regulatory body, the FDA. The therapy was based on the use of a variant of CRISPR tools known as epigenetic editing, to reactivate the mutated dystrophin gene using other regulatory sequences. The treatment was carried out by the company Cure Rare Disease, whose CEO was the brother of the patient with Duchenne, which in itself raised an underlying conflict of interest. He was injected with such a large quantity of viruses carrying the CRISPR tools (based on the doses injected into mice) that his immune system was unable to cope, and he died within a few days, partly due to an unknown predisposition he had which led to immune failure.

This week, through an exclusive report in the journal Science, we have learnt of the case of a Chinese girl with a mild form of a neurological syndrome associated with cognitive impairment and autism. Although this patient did not have a severe form of the condition, she was nonetheless treated with an experimental procedure that had not been sufficiently validated or tested in preclinical stages; this resulted in her death within a few days of receiving the treatment, the substantial cost of which was borne by the family. Once again, a treatment involving a single patient has had fatal consequences. In this case, the patient received a spinal cord infusion containing a huge quantity of viruses carrying a CRISPR base editor designed to correct a single nucleotide in the affected gene expressed in the brain. The researchers had previously published preclinical trials in animals (mice and non-human primates) in which liver and kidney failure had already been observed, leading to recommendations that the procedure be reviewed before proceeding with human subjects. The researchers chose to ignore these preclinical warnings and decided to continue with the experiment, which has ended in the girl’s tragic death.

Single-patient experimental therapies often make big headlines in the media and feature on the news. When they work. These are risky therapeutic procedures, not yet formally approved, in which the safety and efficacy of proposed new treatments are assessed in a single patient, in the absence of any other cure. However, if something goes wrong, we do not usually find out about it, unless the consequences are fatal for the patient and the story makes the headlines again due to the harm caused.

These single-patient therapies leave very little room for interpretation. We can only rejoice when they work as expected. But when they fail to meet expectations, they generate more doubts than certainties, as there is no control case against which to compare them, nor any possibility of comparing the results of different doses or different routes of administration. And, when they result in the death of the treated patient, they raise even more questions and cause distress amongst the patient’s family and the scientific and medical community.

Ethically, they also raise a debate that cannot be ignored, given the decision to devote vast resources to saving the life of a single patient, whilst other patients with the same condition are excluded from the potential benefits of this therapeutic approach. Objectively speaking, it will always be better to organise a clinical trial that meets all the necessary requirements, with well-established phases and formalities, in order to assess the safety and efficacy of an experimental medicine or therapy in a cohort of patients, rather than staking everything on the possible success of a single patient. Nor can we overlook or fail to take into account the problems that arise during the preclinical phases of a therapy’s development, in animal models, which must precisely be included in order to anticipate potential major problems in patients. These preclinical phases are indispensable and must be undertaken and interpreted appropriately. There are no shortcuts in the development of therapies.